The incidence of microbial infections (e.g., mycobacterial, fungal and protozoal infections) in the immunocompromised population has significantly increased over the past several years. In particular, Candida species, especially Candida albicans, are often significant pathogens in patients infected with human immunodeficiency virus (HIV). Another pathogen, Pneumocystis carinii, causes a form of pneumonia (PCP) that is believed to be one of the leading causes of death in patients suffering from AIDS.
Human African trypanosomiasis (HAT) has reemerged as a threat to over 60 million people. Current estimates are that between 350,000 and 450,000 people are infected.
Other severe and life-threatening microbial infections are caused by Mycobacterium tuberculosis, Aspergillus spp., Cryptosporidium parvum, Giardia lamblia, Plasmodium spp., Toxoplasma gondii, Fusarium solani, and Cryptococcus neoformans. 
The antimicrobial properties of dicationic molecules have been studied since the 1930's. Compounds of this type have typically utilized amidine groups as the cationic moieties, and their activities against a number of pathogens including Cryptosporidium parvum, Giardia lamblia, Leishmania spp., Plasmodium spp., Pneumocystis carinii, Toxoplasma gondii, Trypanosoma spp., Candida albicans, Aspergillus spp., and Cryptococcus neoformans have been reported. See e.g., King, H. et al., Ann. Trop. Med. Parasitol. 1938, 32,177-192; Blagburn, B. L. et al., Antimicrob. Agents Chemother. 1991, 35, 1520-1523; Bell, C. A. et al., Antimicrob. Agents Chemother. 1991, 35, 1099-1107; Bell, et al., Antimicrob. Agents Chemother. 1990, 34, 1381-1386; Kirk, R. et al., Ann. Trop. Med. Parastiol. 1940, 34, 181-197; Fulton, J. D. Ann. Trop. Med. Parasitol. 1940, 34, 53-66; Ivady, V. G. et al., Monatschr. Kinderheilkd. 1958, 106, 10-14; Boykin, D. W. et al., J. Med. Chem. 1995, 38, 912-916; Boykin, D. W. et al., J. Med. Chem. 1998, 41, 124-129; Francesconi et al., J. Med. Chem. 1999, 42, 2260-2265; Lindsay, D. S. et al., Antimicrob. Agents Chemother. 1991, 35, 1914-1916; Lourie, E. M; et al., Ann. Trop. Med. Parasitol. 1939, 33, 289-304; Lourie, E. M. et al., Ann. Trop. Med. Parasitol. 1939, 33, 305-312; Das, B. P. et al., J Med. Chem. 1976, 20, 531-536; Del Poeta, M. et al., J. Antimicrob. Chemother. 1999, 44, 223-228; Del Poeta, M. et al., Antimicrob. Agents Chemother. 1998, 42, 2495-2502; Del Poeta M. et al., Antimicrob. Agents Chemother. 1998, 42, 2503-2510.
Despite the broad range of activity exhibited by diamidines, only one compound of this chemical type, pentamidine, has seen significant clinical use. Pentamidine has been used clinically against African trypanosomiasis, antimony-resistant leishmaniasis and P. carinii pneumonia See e.g., Apted, F. I. C., Pharmacol. Ther. 1980, 11, 391-413; Bryceson, A. D. M. et al., Trans. Roy. Soc. Trop. Med. Hyg. 1985, 79, 705-714; Hughes, W. T.; et al., Antimicrob. Agents Chemother. 1974, 5, 289-293.
A number of compounds in this class of dicationic molecules have been shown to bind to the minor-groove of DNA at AT-rich sites and the details of their interaction with the minor-groove have been elucidated from biophysical studies and from several crystal structures. It is hypothesized that these types of molecules exert their biological activity by first binding to DNA and then by inhibiting one or more of several DNA dependent enzymes (i.e., topoisomerases, nucleases, etc.) or possibly by direct inhibition of transcription. See, Tanious, F. A. et al., J. Biomol. Struct. & Dyn. 1994, 11, 1063-1083.; Wilson, W. D. et al., J. Am. Chem. Soc. 1998, 120, 10310-10321; Bailly, C. et al., Anti-Cancer Drug Design, 1999, 14, 47-60; Mazur, et al., J. Molecular Biology 2000, 300, 321-337; Trent, J. O.; et al., J. Med. Chem. 1996, 36, 4554-4562; Guerri, A. et al., Nucleic Acids Res. 1998, 26, 2873-2878; Laughton, C. A. et al., Biochemistry 1996, 35, 5655-5661; Beerman, T. A. et al., Biochim. Biophys. Acta 1992, 1131, 52-61; Bell, C. A.; et al., Antimicrob. Agents Chemother. 1993, 37, 2668-2673; Dykstra, C. C. et al., Antimicrob. Agents Chemother. 1994, 38, 1890-1898; Hildebrandt, E. et al., J. Euk. Microbial. 1998, 45, 112-121; Henderson, D. et al., Nature Medicine 1995, 1, 525-527; Fitzgerald, D. J.; et al., J. Biol. Chem 1999, 274, 27128-27138.
2,5-Diphenylfuran and 2,4-diphenylfuran diamidines have been found to be highly effective treatments in animal models for Pneumocystis carinii and Cryptosporidium parvum. See Blagburn, B. L. et al., Antimicrob. Agents Chemother. 1991, 35, 1520-1523; Boykin, D. W. et al., J. Med. Chem. 1995, 38, 912-916; Boykin, D. W. et al., J. Med. Chem. 1998, 41, 124-129; Francesconi, I. et al., J. Med. Chem. 1999, 42, 2260-2265; Tidwell, R. R. J. Parasitol. 1998, 84, 851-856. Furthermore, these molecules have shown antifungal activity in vitro against Candida albicans and Cryptococcus neoformans. See, Del Poeta, M. et al., J. Antimicrob. Chemother. 1999, 44, 223-228; Del Poeta, M. et al., Antimicrob. Agents Chemother. 1998, 42, 2495-2502; Del Poeta, M. et al., Antimicrob. Agents Chemother. 1998, 42,2503-2510.
Although there are reports of antimicrobial activity of guanidino compounds, this class of cationic compounds has not been studied as extensively as their amidino analogs. See Lourie et al., Ann. Trop. Med. Parasitol. 1937, 31, 435-445.